Presence and severity of migraine is associated with development of primary open angle glaucoma: A population-based longitudinal cohort study

Purpose To examine the association between the presence and severity of migraine and development of primary open-angle glaucoma (POAG) using a nationwide population-based longitudinal cohort data. Methods Data were retrieved from the Korean National Health Insurance Service for 2,716,562 individuals aged ≥ 40 years and assessed for the development of POAG from 2009 through 2018. Subjects were classified into the following 3 groups: healthy control subjects, subjects with mild migraine, and those with severe migraine. Hazard ratios (HR) of glaucoma development were calculated for each group. Subgroup analyses of subjects stratified by age, sex, lifestyle factors (smoking, drinking, and body mass index (BMI)), and comorbidities (diabetes, hypertension, and dyslipidemia). Results During the 9-year follow-up period, the incidence rate of POAG per 1000 person-years was 2.41 and 3.25 in subjects without and with migraine, respectively. Among the migraine group, the incidence rate was 3.14 and 3.89 in mild and severe subgroups, respectively. The HR was 1.355 (95% CI, 1.300–1.412) and 1.188 (95% CI, 1.140–1.239) before and after adjusting for potential confounding factors in the migraine group per se. Regarding the severity of migraine, the adjusted HRs were 1.169 (95% CI, 1.117–1.224) in the mild migraine group, and 1.285 (95% CI, 1.166–1.415) in the severe migraine group compared to the control group. The results were consistent in subgroup analyses after stratifying by age, sex, lifestyle factors, and comorbidities. Conclusions Migraine is associated with increased risk of POAG development. Furthermore, chronic and severe migraine is associated with greater risk of POAG development.


Introduction
Migraine affects more than 10% of the adult population worldwide and it ranks among the world's most disabling medical illnesses [1]. In addition, the economic and societal effect of migraine is substantial: it affects patients' quality of life and impairs work, social activities, and family life [2][3][4]. Although the nature and mechanism of migraine are complex and remain incompletely understood, potential mechanisms include vasospasm, vascular endotheliumrelated hypercoagulability, and vascular changes related with cortical spreading depression [5,6]. Migraine is considered a systemic vasculopathy and is associated with ischemic heart disease, stroke, and other cardiovascular diseases [6].
This association seems even stronger in those with normal tension glaucoma (NTG) [23], which is the most prevalent type of glaucoma in Korea. The proportion of NTG among POAG patients in Korea was 77% in the Namil epidemiologic study [24]. Therefore, we included the patients with NTG into the subject population of the present study to better represent the epidemiologic situation in Korea.
Considering this common etiology, a potential association between migraine and primary open angle glaucoma (POAG) has been previously studied, but the results are inconclusive. The Blue Mountains Eye Study demonstrated a positive association between migraine and POAG among those aged 70-79 [25]. In contrast, the Beaver Dam Eye Study found that there was no evidence of a relationship between open-angle glaucoma and migraine [26]. In a metaanalysis investigating the association between migraine and glaucoma, a significant association was found in case-control design studies, but not in cohort design studies, and the authors concluded the association is still controversial [27]. In addition, no study has explored the risk of glaucoma according to the severity of migraine.
Therefore, this study investigated the association between migraine and increased risk of developing POAG over a 9-year follow-up period using a nationwide longitudinal cohort data. We also examined whether this potential association was proportional with the chronicity and the severity of migraine. diagnosis, medical treatment), history of comorbid diseases (e.g., hypertension, dyslipidemia, stroke, diabetes mellitus), and demographics (e.g., age, sex, household income) of patients. In addition, KNHIS also provides a standardized health screening program to all Koreans aged 40 or more. The KHED includes anthropometric data and laboratory tests. The KNHIS provides de-identified data to medical researchers who meet the access criteria.
This study was approved by the Institutional Review Board of Yeouido St. Mary's Hospital, Seoul, Korea (SC21ZISE0175). Informed consent was waived by the IRB. This study was a retrospective cohort study, and all data were fully anonymized by the KNHIS before assessed by researchers. This study adhered to the Declaration of Helsinki.

Exposure determination and outcome measurement
The exposure of interest was migraine diagnosis. Diagnosis for migraine was defined as at least one KNHIS claim under International Classification of Diseases (ICD)-10 code for migraine (G43) in 2009 (index year). Regarding the severity of migraine, subjects without chronic and severe migraine were further stratified into the "mild" group and those with chronic and severe migraine were categorized into the "severe" group. Chronic migraine was defined as diagnosis of migraine more than twice at least 3 months apart. Severe migraine was defined as follows: i) at least one hospitalization for migraine as the main diagnosis, ii) at least one visit to the emergency room for migraine as the main diagnosis, iii) Triptans (N02CC) and ergots (N02CA) are administered at least once within 1 year from the time of diagnosis, iv) perform the following procedures at least once within 1 year from the time of diagnosis: MM070, LA210, LA222, LA223, LA224, LA225, LA226, LA227, LA228, S0471, S0472, S0474, S0475, S0476, S0477, S0478, S4730, SZ636, SZ637, SZ638, or SZ639.
The outcome of interest was POAG. Development of POAG was defined as KNHIS claims with ICD-10 code for POAG (H401). The ICD-10 code H401 includes POAG and NTG. To strengthen the diagnostic validity, only those with at least three outpatient visits for glaucoma a year were included [28]. To establish a temporal and causal relationship between migraine and POAG, those with prior diagnosis of POAG before the index year and those who were diagnosed within one year after migraine diagnosis were excluded.

Statistical analysis
The Student's T-test was used to compare continuous variables between groups, and the Chisquare test was used to compare categorical variables. Cox's proportional hazard regression was performed to estimate the hazard ratios for various risk factors. Hazard ratio for exposure of interest, history of migraine, was calculated using three models: model-1, un-adjusted; model-2, adjusted for age, sex, smoking habits, drinking habits, frequency of exercise, household income; model-3, adjusted for comorbid disease status (diabetes, hypertension, dyslipidemia, body mass index, and glomerular filtration rate), along with all risk factors addressed in model-2. Incidence probabilities of POAG to migraine was calculated using Kaplan-Meier survival analysis. All statistical analyses were performed using SAS (Version 9.4; SAS Institute, Cary, NC, USA). p-values � 0.05 were considered statistically significant.  Table 1 presents the demographic characteristics, medical conditions, and laboratory test results of subjects in study population. Compared to subjects without history of migraine, subjects diagnosed with migraine were more likely to be female, non-smoker, non-drinker, had higher prevalence of hypertension, dyslipidemia, myocardial infarction, chronic heart failure, and stroke. Apart from that, we found small but statistically significant differences in age, sex, exercise, income, glomerular filtration rate (GFR), body mass index (BMI), waist circumference, systolic/diastolic blood pressure, and blood level of glucose, total cholesterol, high/low density lipoprotein, triglyceride, γ-glutamyl transpeptidase, aspartate transaminase, and alanine transferase between those with and without migraine.

Study population
The risk of POAG among the study subjects during the 9-year follow up Table 2 shows the incidence and hazard ratio (HR) of POAG according to migraine status. The incidence rate per 1000 person-years was 2.408 and 3.249 in subjects without and with migraine, respectively. Among the migraine group, the incidence rate was 3.137 and 3.893 in mild and severe groups, respectively. The HRs calculated using model-1, model-2, and model-3 were 1.355 (95% confidence interval [CI]: 1.300-1.412), 1.202 (95% CI: 1.153-1.253), and 1.188 (95% CI: 1.140-1.239), respectively. Cumulative incidence of POAG according to history of migraine is illustrated in Fig 2. The log-rank test showed that subjects with migraine had significantly higher POAG development rates compared with those without (P< 0.001). In addition, a subgroup analysis was performed to further elucidate the impact of migraine severity on development of POAG. HR was greater when migraine was chronic and severe. HRs for subjects with mild migraine compared to those without migraine were 1.306 (95% CI: 1.248-1.367), 1.181 (95% CI: 1.128-1.236), and 1.169 (95% CI: 1.117-1.224) and those with severe We further conducted a risk-stratified analysis to further quantify the impact of migraine in specific patient subgroups. Tables 3 and 4 presents HRs of POAG in subgroups stratified according to subjects' age, sex, BMI, smoking/drinking habits or presence of diabetes/hypertension/dyslipidemia. The association between migraine and subsequent POAG was consistent in all subgroup analyses. The association of migraine with development of POAG differed according to age (P for interaction = 0.004) and HTN (P for interaction = 0.001) ( Table 3). The impact of migraine on POAG development was greater in the younger group (aHR: 1.235, 95% CI: 1.168-1.305) compared to those aged 65 or older (aHR: 1.139, 95% CI: 1.069-1.214). In addition, the aHR of POAG diagnosis during the 9-year follow-up period was greater in those without hypertension (aHR: 1.261, 95% CI:1.186-1.341) compared to those with hypertension (aHR: 1.128, 95% CI:1.066-1.194) Similar pattern was noted when subjects with chronic and severe migraine were classified into a subgroup (Table 4).

Discussion
We found that subjects with migraine were independently associated with a 1.19 times increased risk of POAG diagnosis after adjusting for age, sex, smoking, drinking, exercise, income, diabetes, hypertension, dyslipidemia, body mass index, and glomerular filtration rate within 9 years after their diagnosis. While those with mild migraine showed 1.17 times greater risk, those with severe and chronic migraine showed 1.29 times greater risk of POAG after adjusting for confounding factors.
Migraine is an episodic neurologic disorder characterized by recurrent attacks of throbbing headache and typical premonitory features such as nausea or sensory hypersensitivity. The development of symptoms are related with the activation of trigeminovascular system and cortical spreading depression, although underlying mechanisms are still up for discussion [5]. It is noteworthy that glaucoma shares certain characteristics with migraine in that both are possibly associated with vascular dysregulation in terms of pathophysiology of the diseases [29,30]. Moreover, vasospasm intensity, calculated based on the presence or absence of migraine, cold extremities and vasospastic response to temperature change, is strongly associated with the development of the disease in particular subgroups of glaucoma [31]. Broadway and Drance [31] discovered that glaucoma patients with focal ischemia of the optic nerve head and subsequent focal loss of the neuroretinal rim had a higher prevalence of vasospasm and migraine than glaucoma patients without these forms of optic tissue destruction. Whether migraines can significantly increase the risk of developing POAG is still controversial. For example, Lin et al. [32]. reported that subjects with migraine were more likely to have POAG compared with those without migraine, even after adjusting for gender, age, monthly income, and level of urbanization of the community. The Collaborative Normal-Tension Glaucoma Study Group analyzed the risk factors for deterioration of visual field defects in NTG and found migraine to be an independent risk factor for more rapid progression [11]. Huang et al. [33] found that migraine is associated with a higher risk of open angle glaucoma in patients with no comorbidity who are aged under 50 years. Motsko et al. reported migraines were found to be independent risk factors for the development of OAG [34]. Also, other previous studies found significant association between migraine and POAG [35,36]. On the other hand, some studies reported that migraines did not increase the risk of POAG [37][38][39]. Landers et al. found there was no significant association between migraine and POAG after adjusting for confounders [39]. We believe that diverse study designs and ethnic populations may be contributing to the disparities among studies. Prevalence of migraine and POAG both increase along with the subjects' age. It was consistently reported that migraine remained to be a significant risk factor for the development of POAG when the relative risk was adjusted for the subjects' age [27,33]. To corroborate this observation, we performed a risk-stratified analysis in our study (Tables 3 and 4). Notably, when the subjects were divided into two age groups, the impact of migraine on the development of POAG was greater in those who were younger than 65 compared to those aged 65 or older. In addition, we also found that migraineurs without comorbid hypertension showed higher risk of POAG than those with hypertension. Further research is warranted to clarify our findings.
Previously, Huang et al. [33] also reported that the cumulative incidence of POAG was significantly higher among the migraineurs compared to normal control subjects. However, because it was not possible to perform a subclassification of migraine group in their study, the relationship between glaucoma progression and migraine severity was not addressed. To shed light on this, we subclassified subjects with migraine based on chronicity and severity of migraine based on the frequency and type of insurance claims. It is worth to note that we saw stronger evidence of association between migraine and POAG, when the course of migraine was worse (Table 2).
Our study has the following strengths. First, the sample size is large enough to jointly evaluate the impact of migraine on the development of POAG, with the effect of other variables including age, sex, smoking or drinking habits, socioeconomic status, and comorbid diseases. In addition, we aimed to establish a temporal and causal relationship between migraine and POAG onset using this longitudinal database by excluding those previously diagnosed with POAG before or within one year after the index year. Secondly, we only included those with medically diagnosed migraine and POAG rather than self-questionnaires, thereby increasing the validity of the study subjects. Thirdly, although confined to Koreans, the study population of the present study well represents the actual population composition of the entire country, given that it is an obligation to join the KNHIS for all individuals in South Korea.
Our study also has some limitations. All data were collected from KHED and NHID, which originally were not established with the sole intention of being used for research purpose which might have led to some limitations. First, people with undiagnosed glaucoma were not included in our estimates of glaucoma prevalence, which may have resulted in an underestimated prevalence. Second, national claims data do not always match hospital chart records. It has been shown that national claims data and hospital records only have a 70-80% concordance rate [40]. We attempted to mitigate this by including only those with at least three visits under the diagnosis of glaucoma, but this may have affected our results. Third, we haven't excluded or controlled for different classes of antihypertensive medication which can be associated with glaucoma development or progression. Some studies found that antihypertensive drugs seem to reduce the risk of developing glaucoma [41]. On the other hand, others found that antihypertensive medication compromises optic nerve head blood flow which may lead to a higher risk of glaucomatous progression [42,43]. Finally, the degree of migraine can vary depending on the medication, however, we have not included the effect of migraine medication on chronicity and severity of migraine in the subanalysis. Also, the clinical information about glaucoma medication, glaucomatous optic neuropathy and visual field defects were unavailable and measurement and adjustment for factors a priori known to be associated with the POAG, such as intraocular pressure, might strengthen the importance of our findings.

Conclusion
In conclusion, our study suggests that presence and severity of migraine are both associated with increased risk of subsequent development of POAG. We found that the hazard of POAG development was 1.19 times greater in subjects with migraine compared to those without after adjusting for age, sex, lifestyle factors, and comorbidities. Furthermore, we also found that subjects with chronic and severe migraine showed 1.29 times greater hazard of POAG development. It is recommended that neurologists refer migraineurs for glaucoma assessment, especially when migraine is chronic and severe.